Mechanism of Divalent-Ion-Induced Charge Inversion of Bacterial Membranes

Abstract

The surface charge inversion (CI), critical for functions of many biological nanomachinery, is a counterintuitive phenomenon in which the net charge of a strongly charged surface bound with many counterions changes its sign. Many phenomena of CI cannot be explained in the framework of mean-field theories, such as linear Debye-Hückel and nonlinear Poisson-Boltzmann, and is so far best described by the strongly correlated liquid (SCL) theory for multivalent (Z ≥ 3) ions. However, the potential CI by divalent ions, which are more relevant in the biological environment, is much less studied and remains mostly illusive. In this study, we examine the divalent-ion-induced CI of a negatively charged bacterium's cell membrane and reveal its underlying mechanism, using all-atom molecular dynamics simulations and free energy perturbation theory. Our simulation results are compared with theoretical predications from SCL, and noticeable discrepancies with SCL theory, originating from the fluidity of membrane lipids whose negatively charged PO4- groups aggregate around adsorbed Ca2+, are found. Our simulation data suggest that the CI of the bacterial membrane results from the strong binding of Ca2+ to the membrane's phosphate groups via an induced-fit mechanism, forming positively charged Ca2+-centered clusters that replace originally negatively charged lipids.